To link to the entire object, paste this link in email, IM or documentTo embed the entire object, paste this HTML in websiteTo link to this page, paste this link in email, IM or documentTo embed this page, paste this HTML in website

The effect of tumor-mediated immune suppression on prostate cancer immunotherapy

THE EFFECT OF TUMOR-MEDIATED IMMUNE SUPPRESSION ON PROSTATE
CANCER IMMUNOTHERAPY
by
Andrew Gray
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2011
Copyright 2011 Andrew Gray

Immunotherapy has long been proposed as a novel method of specifically, safely and inexpensively treating cancer. Despite decades of research and hundreds of clinical trials, only one therapeutic cancer vaccine has been approved for human use. The vast majority of these clinical trials have been carried out in terminally ill patients with advanced cancer. These patients are severely immune compromised. The studies herein demonstrate that multiple immunosuppressive mechanisms develop within prostate tumors as they progress. These mechanisms include the accumulation of regulatory T cells in the prostate tumor, and increased expression of TGFβ and indoleamine 2,3 dioxygenase in the prostate tumor. Vaccination of mice with spontaneously arising prostate cancer against tumor-associated antigens is vastly superior to immunization at later stages of disease, when tumor microenvironments are more suppressive. A novel murine model of prostate cancer in which major mediators of immune suppression – FOXP3-expressing regulatory T cells – can be specifically depleted was developed. This model was termed the TRAMP DEREG mouse. Depletion of regulatory T cells improved the response to therapeutic cancer vaccinination in TRAMP DEREG mice. This was the case even though Treg depletion was carried out at a phase of carcinogenesis prior to the development of serious immune suppression, suggesting that even better results can be obtained if Tregs are inhibited when they are most prevalent in immunosuppressive prostate tumors. Prostate cancer stem cells are responsible for driving tumor growth and regeneration. Additionally, they do not express the tumor-associated antigens that are targeted in prostate cancer immunotherapy, thus rendering them resistant to immune-medidated eradication. An effort was made to eliminate this population by inhibition of Notch signaling, but it was found that Notch signaling is not involved in the maintenance of the prostate cancer stem cell phenotype. In addition, Notch inhibition severely limited the efficacy of concomitant therapeutic cancer vaccination. However, the novel finding that Notch signaling is critical to the differentiation of prostate cancer cells, and thus to tumor growth and regeneration, is extremely important. Taken together, these studies show that immune-mediated tumor eradication is extremely difficult to achieve in advanced cancer. Therefore it is proposed that clinical trials of cancer immunotherapies be carried out in the preventative setting as soon as possible.

The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given.

THE EFFECT OF TUMOR-MEDIATED IMMUNE SUPPRESSION ON PROSTATE
CANCER IMMUNOTHERAPY
by
Andrew Gray
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2011
Copyright 2011 Andrew Gray